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Complement System01:27

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The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
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The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
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T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
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Intracellular sensing of complement C3 activates cell autonomous immunity.

Jerry C H Tam1, Susanna R Bidgood1, William A McEwan1

  • 1Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.

Science (New York, N.Y.)
|September 6, 2014
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Cells detect invading pathogens like viruses and bacteria using complement C3, triggering immune responses and degradation. Certain viruses cleave C3, but an antiviral drug restores this defense mechanism.

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Area of Science:

  • Immunology
  • Cell Biology
  • Virology

Background:

  • Pathogens must overcome cellular barriers to establish infection.
  • Intracellular pathogen detection is crucial for effective host defense.
  • The complement system is a key component of innate immunity, primarily acting extracellularly.

Purpose of the Study:

  • To investigate the role of complement C3 in intracellular pathogen detection.
  • To elucidate the signaling pathways activated by intracellular C3.
  • To identify mechanisms by which pathogens evade intracellular complement sensing and explore potential therapeutic interventions.

Main Methods:

  • Tracking pathogen entry and C3 localization using fluorescent microscopy.
  • Analyzing intracellular signaling cascades via Western blotting and cytokine assays.
  • Assessing pathogen replication and degradation using quantitative PCR and proteasomal activity assays.
  • Investigating the effect of viral proteases and antiviral compounds on C3 function.

Main Results:

  • Pathogens carrying covalently attached complement C3 into the cytosol trigger immediate intracellular signaling.
  • Cytosolic C3 activates mitochondrial antiviral signaling (MAVS)-dependent pathways, inducing proinflammatory cytokine secretion.
  • C3 flags intracellular pathogens for proteasomal degradation, inhibiting replication.
  • Enteroviruses, such as rhinovirus and poliovirus, antagonize this system by cleaving C3 via their 3C protease.
  • The antiviral rupintrivir inhibits viral 3C protease, preventing C3 cleavage and restoring susceptibility to intracellular complement sensing.

Conclusions:

  • Complement C3 functions as an intracellular sensor for invading pathogens, initiating rapid immune responses.
  • Intracellular C3-mediated sensing and degradation represent a novel host defense mechanism against viral and bacterial infections.
  • Targeting viral proteases can overcome pathogen evasion strategies, rendering them vulnerable to intracellular complement-mediated immunity.